Abstract

In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10-14 weeks to convert to everolimus (n=359) or remain on standard calcineurin inhibitor (CNI) therapy (n=356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated GFR from randomization to month 12, was similar for everolimus versus CNI: mean (SE) 0.3(1.5)mL/min/1.732 versus -1.5(1.5)mL/min/1.732 (p=0.116). At month 24, mean (SD) estimated GFR was 62.5(22.4)mL/min/1.73m2 with everolimus and 57.4 (19.9) mL/min/1.73m2 with CNI (p=0.005), and 59.7(20.5)mL/min/1.73m2 and 53.0(18.0)mL/min/1.73m2 , respectively, for the tacrolimus- and cyclosporine-treated CNI subgroups. BPAR at month 12 was more frequent under everolimus versus CNI overall (9.7% versus 4.8%, p=0.014) and versus tacrolimus-treated patients (2.6%, p<0.001) but similar to cyclosporine-treated patients (8.8%, p=0.755). Reporting on de novo donor specific antibodies (DSA) was limited but suggested more frequent anti-HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10-14 weeks post-transplant was associated with similar renal function to standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus thaneverolimus. This article is protected by copyright. All rights reserved.

COMMENTS:

From this and previous studies, I can see little advantage, and possible disadvantages from CNI to mTOR inhibitors (mTORi) conversion in renal transplantation.

Beside marginally better renal function, that can be ascribed to CNI withdrawal rather than mTORi substitution,https://www.ncbi.nlm.nih.gov/pubmed/25088685

it would seem that mTORi are associated with more biopsy proven acute rejections (BPAR) as also shown in the SOCRATES study: https://www.ncbi.nlm.nih.gov/pubmed/24279685

Combination therapy with mTORi and low dose CNI therapy has also been advocated rather than total discontinuation of CNI as in the ELEVATE study. This may attenuate the risk of DSA and associated chronic AMR: https://www.ncbi.nlm.nih.gov/pubmed/25040585

The long-term positive effects of mTORs on CV system should not be ignored, Patients who are immunologically low risk may be candidate for mTORs. In my humble opinion, treatment decision for immunosuppresive drugs should not only be determined according to immunologic status, CV status carefully be take in to account.

In the light of those evidences, I think, we may use mTOR inh to the patients who are immunological low risk but have high CV risk
Should we wait randomize controlled studies to use that drug in that area

what does this have to do with CVD risk reduction in CKD....or in renal transplant recipients....?!

Statins reduce CAD mortality in the general population...but not in CKD!

Raised hemoglobin and its normalisation reduce LVH...but not in CKD!

ELEVATE refers to patients who underwent renal transplantation; therefore references should refer to those rather than make blanket statements about the CVD risk reduction associated with mTORi eluting stents...???!!!!!

Maybe a role for low risk patients who can't tolerate CNIs .... but this is a disappointing class of drug... higher BPAR, increase in DSA, high no of people who simply can't take the drug (23%), worse outcomes in registry data...

1. 40% of patients do not tolerate, this has been a fairly consistent figure across a range of studies including primary and secondary use of the drugs
2. They do not provide as good protection from rejection as full dose CNI, especially humoral rejection and development of de novo HLA specific antibodies. This seems particularly true in combination with alemtuzumab although the awaited medium term results of 3C may clarify this.
3. The proteinuria issue that you are all familiar with.

I have never been convinced that the marginal GFR gain that you see using mTORs in patients with good grafts are meaningfully beneficial. The very patients you want to use it in, those with less good grafts that are susceptible to CNI toxicity, do not do well with mTORi (eg the CONVERT study Schena FP et al Transplantation 2009;87:233-42).

The CV benefits in clinical practice are hard to be sure about. If you are in an mTORi and get rejection or proteinuria, you are almost certainly worse off from a CV perspective.

mTORi will remain a niche drug in my view. There are a small number of patients who tolerate it well and for whom getting off CNI is a very high priority for whatever reason (KS, other malignancy, intolerable toxicity such as alopecia in females on Tac, disproportionately severe renal CNI toxicity in a patient with reasonably preserved eGFR). For these patients, it can be a good option, but warn them that there is a 40% chance they will not tolerate before you switch. As a blanket strategy, I do not believe it is a good option.